Jeremy D. Coplan, MD

Anxiety disorders are the most prevalent psychiatric disorders in the United States. Although effective treatments are available, such as the SSRIs and cognitive-behavioral therapy (CBT), it is estimated that in about 40% of patients, anxiety disorders are partially or completely resistant to first-line treatment.

 The underlying causes of such high rates of treatment resistance are unclear, but these patients are likely to pose a major challenge for psychiatrists, since most first-line treatments are administered by nonpsychiatric physicians, whereas refractory anxiety disorders are the domain of psychiatrists.

A large overlap between major depression and anxiety disorders has been noted, both in terms of phenomenology and treatment response.

 Thus, tricyclic antidepressants and monoamine oxidase inhibitors are each effective in generalized anxiety disorder (GAD) and panic disorder. SSRIs are effective antidepressants that have also been found to be efficacious in GAD, panic disorder, social anxiety disorder, and obsessive-compulsive disorder.

It is important to recognize which forms of depressive disorders are resistant to antidepressants. Some examples include bipolar depression

 Anxiety disorders, when comorbid with mood disorders, are as likely to be comorbid with bipolar disorder as with unipolar disorders.

 It has been hypothesized that childhood depression and anxiety may represent a variant in presentation of an underlying bipolar disorder.

 Therefore, a precedent is suggested whereby anxiety disorders may mimic certain variants of mood disorders and become treatment resistant.

A recent neurobiologic substrate has been identified for treatment resistance in anxiety disorders. Findings from a study by Stein and colleagues

 suggest that patients with generalized social anxiety disorder (GSAD) who had the "short"arm of the serotonin transporter gene were significantly less likely to respond (40% nonresponders) to maximally titrated SSRIs than patients with the "long"arm of this gene. Similar genetic variants relating to SSRI treatment resistance have been noted for panic disorder.

 It is not clear what the functional consequences of possession of the short versus long arm of the serotonin transporter imply; however, we posit that treatment-resistant anxiety disorders result from both an excess and a deficit of synaptic serotonin.

Management of treatment-resistant anxiety disorders associated with unipolar and bipolar disorders

Only 1 in 5 physicians diagnosed bipolar disorder correctly using the Mood Disorder Questionnaire.

 The remaining 80% of psychiatrists incorrectly diagnosed anxiety disorder, mood disorders, and personality disorder. We would argue that an anxiety disorder, when comorbid with bipolar mood disorder, should not be subsumed under the bipolar diagnosis, but rather the term "bipolar anxiety disorders"may encompass both the mood and anxiety disorder components simultaneously. Anxiety disorders were highly prevalent in bipolar subjects compared with controls (49 [61%] vs 7 [14%]).

Bipolar I disorder is usually readily recognized, whereas bipolar II disorder comorbid with anxiety disorders can represent a clinical challenge for even the experienced psychiatrist.

 The patient with a treatment-resistant anxiety disorder is only likely to fully respond to treatment when pharmacotherapy that is also effective for bipolar disorder is instituted. Perhaps the most difficult challenge is the diagnosis of subtle forms of bipolar spectrum disorder, in which hypomania may present as maladaptive versus adaptive.

 Red flags include racing thoughts, irritability, late-night multitasking, and insomnia. Psychosomatic conditions, including fibromyalgia and migraine headache, appear to be associated with bipolar anxiety.

An examination of mood response to occupational and recreational activities in the patient who has treatment-resistant anxiety disorder is warranted. We cite the example of 3 firefighters who survived ground zero on September 11, 2001. Exposure to extreme trauma led to PTSD in each firefighter. Treatment with SSRIs, adjunctive benzodiazepines, and skilled ad- ministration of CBT failed to achieve a treatment response.

Only after several months of treatment resistance did we specifically inquire, and integrate into our treatment plan, the occurrence of manic symptoms. None of the 3 firefighters had had any prior history of bipolar disorder. One firefighter reported a frank manic episode for 2 weeks after 9/11, followed by the full syndrome of PTSD. All 3 patients endorsed a similar state of profound mood alteration following the dousing of a fire--a state of euphoria, elation, and perception of omnipotence. Each of the 3 responded markedly well to the addition of lamotrigine to their SSRI regimen, with clear reductions in PTSD symptomatology.

Another example is of a young man who presented with classic panic disorder, and failed to respond to treatment with either sertraline or paroxetine, along with benzodiazepines. His mother reported that the patient had been very moody as a child, alternating between periods of several weeks of elevated mood and depression. An online gambling addiction developed precipitously, causing the patient to incur excessive debt.

During nocturnal gambling periods, the patient experienced racing thoughts, elation, a sense of omnipotence, and a sense of possessing special faculties. Once he had finally acknowledged his gambling losses, he plummeted, over a period of minutes, into a severe state of despondent mood, eventually experiencing severe depression and suicidal ideation and intent. He responded to addition of lamotrigine to his regimen of paroxetine and clonazepam.

A further example is of a middle-aged woman with GAD, who was intolerant of most SSRIs. She had responded to fluvoxamine several years previously but had gradually become increasingly symptomatic. She reported severe generalized anxiety, which was accompanied by irritability, racing thoughts, and increased distractibility. She had begun to pursue nocturnal hobbies, which induced a marked hedonic response and frantic multitasking. She was not tired, and could not bring herself to go to sleep. She believed she had bipolar disorder and raised her concerns with the treating psychiatrist who instead stated that her diagnosis was a unipolar disorder. Eventually, she responded well to the addition of quetiapine and lamotrigine.

Another clinical challenge is the co-occurrence of bipolar disorder and GSAD.

 An elderly woman presented with significant Parkinson disease and generalized anxiety accompanied by major depression. During the history workup, she described herself as extroverted, having enjoyed a career as a performing artist for many years. She reported periods of euphoria, pressured speech, racing thoughts, and a sense of omnipotence. She reported that as a child she had been extremely socially anxious, to the point of selective mutism. On careful inquiry, it emerged that before her performances, she continued to suffer from extreme social anxiety, avoiding all contact with her colleagues. Within seconds of appearing on stage, all social anxiety disappeared and she felt elated and euphoric as she performed. Within minutes following the performance, she lapsed back into her usual social anxiety. She was intolerant of SSRIs and lamotrigine exacerbated the Park- inson disorder; however she responded well to the atypical antipsychotic quetiapine.

If SSRIs have previously been administered, without much evident success, the task at hand is to carefully examine the patient's course during the SSRI trials. We have observed several scenarios in which a patient's anxiety disorder has not responded to SSRI therapy.

In the first situation the SSRI prescribed for an anxiety disorder induces mania, hypomania, rapid cycling, or mixed states. In most instances, a history of a bipolar mood disorder, if not noted previously, can be elicited on more thorough inquiry. According to 

 this form of bipolarity does not definitively indicate bipolar disorder, but, in our experience, predicts a positive response to treatments used for bipolar depression, including atypical antipsychotics and anticonvulsants. Young patients with or at high risk for bipolar disorder may be particularly vulnerable to SSRI antidepressant-induced mania and thus should be closely monitored if given SSRIs. In their preliminary study, Baumer and colleagues

 did not find that serotonin transporter polymorphism significantly influenced vulnerability to antidepressant-induced mania.

In another scenario, the patient is intolerant of the SSRI and a "paradoxic" reaction develops that may include the "jitteriness syndrome." The paradoxic reaction consists of marked sensitivity to the SSRI with development of increased anxiety, jitteriness, or a feeling of "jumping out of one's skin," worsening depression, and irritability. The paradoxic reaction may be responsible for the emergence of suicidal ideation in the context of SSRI administration.

The occurrence of a paradoxic reaction to an SSRI does not bode well for future SSRI treatments, and we include it as a possible side effect when communicating information before we begin treatment with an SSRI. This form of treatment resistance is best managed by starting with an atypical antipsychotic or an anticonvulsant, such as gabapentin or topiramate (although neither is particularly effective in bipolar disorder), or lamotrigine. An SSRI can be added later with reduced likelihood of a paradoxic reaction.

In a third variation, the patient experiences tachyphylaxis or loss of response to the SSRI. Studies by Quitkin and colleagues

 indicated that placebo response was often accompanied by an acute, remitting-relapsing pattern, whereas true drug response was associated with slow and persistent response. Response to SSRIs that mimics the placebo response described by Quitkin and colleagues may follow a similar course of treatment. As occurs with placebo, many patients who experience tachyphylaxis are found to have experienced an initial period of excessively positive mood within days following the initiation of an SSRI. Although bupropion

 has been added to SSRIs to regain treatment response, it is our contention that tachyphylaxis indicates a fundamental inability of serotonin mechanisms to maintain treatment response and requires intervention with agents that work on glutamate (lamotrigine), g-aminobutyric acid (GABA; eg, valproate), serotonin (5-HT)

 receptors (ziprasidone and aripiprazole), histamine (quetiapine, olanzapine, clozapine), and dopamine D

 receptors (atypical antipsychotics as a group).

In yet another situation, the patient experiences very little, if any, response to the SSRI, indicating that attempting to boost synaptic serotonin has failed as a strategy. This may be explained by a biologic model of SSRI treatment resistance (

) based on the work of Commons and colleagues.

 In this model, stress activates neurons in the prefrontal cortex, leading to an increased release of the excitatory amino acid, glutamate, with potential for cytotoxicity.

The hyperglutamatergic state, arising from activation of prefrontal cortical efferent glutamatergic-releasing neurons, has at least 2 effects: first, to stimulate local increase of serotonin in the dorsal raphe. This increase of serotonin activates local 5-HT

 autoreceptors, with the consequence of shutting down raphe neuronal firing, leading to a serotonin deficit state with reduced inhibition of fear-related structures, such as the amygdala.

 Second, glutamatergic stimulation of the amygdala leads to an increased release of the stress neuropeptide, corticotropin releasing factor (CRF), which induces anxiety states when administered to experimental animals. The combined effects of these regional neurochemical changes may contribute to the clinical features observed in human anxiety.

In this model, when an SSRI is administered, since raphe neurons are shut down by glutamate, insufficient synaptic serotonin is available for the therapeutic effect achieved by serotonin reuptake inhibition. In contrast, behavioral effects of stress models in animals are reversible by tianeptine,

 an antidepressant, not available in the United States, that enhances rather than blocks serotonin reuptake.

Treatment resistance and neurotrophic compromise

Comorbid conditions other than mood disorders may complicate the potential treatment response in patients with symptoms of anxiety. These include comorbid alcohol and drug use disorders, somatic conditions such as altered thyroid function, and psychotic disorders such as schizophrenia. At the core of treatment resistance in anxiety disorders may be a process called neurogenesis,

 or formation of new neurons in the hippocampus and other areas of the brain. It has been observed that a host of factors known to exacerbate anxiety disorders and promote treatment resistance also suppress neurogenesis. The precise role of these neurons continues to be debated, with one limitation being that their proliferation is confined to a small area within the hippocampus, the dentate gyrus. However, a number of neurocircuits, inclusive of the prefrontal cortex, anterior cingulate cortex, amygdala, hypothalamus, locus caeruleus, nucleus accumbens, and hippocampus itself, intersect at the dentate gyrus (

Perhaps what is more salient is that the process of neurogenesis is accompanied by maturation of germinal precursor cells that differentiate into new blood vessels (angiogenesis), new glial cells (gliogenesis) that are a critical support for optimal neuronal function, and new oligodendrocytes (oligodendrogenesis), cells that preserve myelin integrity in the white matter of the brain, facilitating communication between neurons.

 Neuroscience is now providing a framework for the clinician, with the possibility that protecting neurotrophism in the brain will become a treatment goal. Some factors that impede neurogenesis and may lead to treatment resistance include hypothyroidism, insulin resistance, sleep deprivation, and inflammation. Factors that stimulate neurogenesis include antidepressants, 5-HT

 agonism, estrogen, valproate, lithium, typical (but not atypical) antipsychotics, and GABA, as well as learning and environmental enrichment.

We recommend the following targeted approach to treatment-resistant anxiety disorders, assuming that the patient is currently taking an SSRI with or without benzodiazepines. First, eliminate any reversible causes, such as stress, substance abuse, sleep deprivation, or hypothyroidism, that may lead to treatment resistance by mediating excitotoxic influences on the brain. Next, block not only serotonin but also norepinephrine. We have reported positive effects by combining SSRIs

 when only partial response was observed with the SSRI alone. The next step is to block glutamate. At present, we have available 2 medications with clear antiglutamatergic properties, lamotrigine and riluzole.

 such as valproate, gabapentin, pregabalin, and topiramate, may be considered at this point but are generally ineffective for comorbid depression. The next strategy is to target the dopamine systems using atypical antipsychotics,

The atypical agents have a host of other effects that may contribute to their anxiolytic properties, including partial 5-HT

 agonism, antihistaminergic effects, anticholinergic effects, and serotonin and norepinephrine reuptake inhibition. Should the use of these agents not be effective, backups include lith-ium, monoamine oxidase inhibitors, buspirone, and electroconvulsive therapy. Other modalities that are being explored include transcranial magnetic stimulation, vagal nerve stimulation, and deep brain stimulation.

It may be that the psychopharmacology of the treatment-resistant anxiety disorder with high comorbidity may occur, figuratively, in layers, with certain symptoms responding earlier than others, necessitating a step-wise strategy to target successive receptor systems. In 

, we schematically integrate a number of central concepts that aim to enlighten the clinician's understanding of the anxious patient's condition, and how ineffective and effective treatment may impact the brain.

With respect to treatment-resistant anxiety disorders, the psychiatrist's role is 3-fold: first, to diagnose bipolar comorbidity; second, to protect neurons from excitotoxicity; and third, to promote neurotrophism.

Dr Coplan is professor of psychiatry and director of the division of neuropsychopharmacology at SUNY Downstate Medical Center in Brooklyn, NY, and director of the nonhuman primate facility. He reports that he is on the Speaker's Bureau for GlaxoSmithKline, BMS, Pfizer Inc, and AstraZeneca; and he has received an investigator initiated grant from Pfizer Inc and GlaxoSmithKline.

Dr Reddy is attending psychiatrist in the division of neuropsychopharmacology at SUNY Downstate Medical Center in Brooklyn, NY. She reports that she has no conflicts of interest concerning the subject matter of this article.

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Jeremy D. Coplan, MD

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Treatment-Resistant Anxiety Disorders: Neurotrophic Perspectives